New designer drugs are often created as alternatives to existing illegal drugs precisely with the intention that they can be sold and marketed with the appearance of legality.
Synthetic cannabinoids, which have similar pharmacology to Tetrahydrocannabinol (THC) the psychoactive ingredient in cannabis, originated as part of research into the cannabinoid receptors CB1 and CB2. Due to their activity at these receptors they have been exploited by drug traffickers and users as legal alternatives to cannabis. Synthetic cannabinoids are generally packaged and sold (under names such as Spice, K2 and herbal incense) as a mixture of an organic carrier medium, usually plant material, which is typically sprayed or mixed with the synthetic compound.
Many of the original compounds commonly found in these mixtures, including JWH-018 and JWH-073, have now been scheduled as illegal drugs in many countries. Clandestine manufacturers and traffickers have responded to these changes in legality simply by producing and distributing synthetic cannabinoid products containing slightly varied compounds in attempts to circumvent these newly created laws.
Among the most recently identified compounds are UR-144 and XLR-11 (Sobolevsky et al 2012; Uchiyama et al 2012; Kavanagh et al 2013). UR-144 and XLR-11 are the new generation of synthetic cannabinoids and are chemically different to the first generation cannabinoids. The napthlene ring in JWH-018 (first generation cannabinoids) is substituted with a tetramethylcyclopropyl group to form UR-144. XLR-11 is the fluorinated version of UR-144. UR-144 ((1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone) is a potent synthetic cannabinoid with preferential binding to the peripheral CB2 receptor over the central CB1 receptor. UR-144 has high affinity for the CB2 receptor with a Ki of 1.8 nM but 83× lower affinity for the CB1 receptor with a Ki of 150. XLR-11 ((1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl) methanone) is an aminoalkylindole compound that is expected to be a cannabinoid mimetic. It is reported that the tetramethylcyclopropyl group confers selectivity for the CB2 over CB1 receptor however the N-(5-fluoropentyl) chain increases binding to both receptors.
UR-144 was added to a temporary class drug schedule in New Zealand on 6 Apr. 2012, while XLR-11 was also added on 13 Jul. 2012. From 11 Dec. 2012 both UR-144 and XLR-11 have been banned in the US state of Florida.
The pharmacological and toxicological effects of many of these synthetic compounds in humans are unknown and unpredictable. They have been reported to cause agitation, anxiety, nausea, vomiting, tachycardia, elevated blood pressure, tremor, seizures, hallucinations, paranoid behaviour and non-responsiveness. XLR-11 and its metabolites have been proposed as the cause in cases of unexplained acute kidney injury (Schwartz et al, 2013).
Current analytical methods use mass-spectrometry (MS) in conjunction with gas chromatography (GC) or liquid chromatography (LC). A disadvantage of such methods of detection is that they require expensive equipment and highly trained staff.
On the other hand, immunoassays are known in the art as relatively cost effective, simplistic and rapid alternatives to mass-spectrometry based analysis. European patent application number 2,487,155 provides immunoassay based methods for the detection of the JWH and CP families of synthetic cannabinoids, however, the antibodies provided in this application show no significant cross-reactivity to UR-144, its metabolites or derivatives. Therefore, there remains a need for an assay which is not only sensitive to the parent molecules of UR-144 and XLR-11 but that can also detect their key metabolites and derivatives to enable improvements in the forensic toxicological and clinical analysis of the intake of these ever evolving designer drugs.
References
Sobolevsky et al., (2012) Drug Testing and Analysis, 4:745-753.
Uchiyama et al., (2012) Forensic Science International, doi:10.1016/j.forsciint.2012.08.047
Schwartz et al., (2013) Centers for Disease Control and Prevention, MMWR; 62:93-98.
Kavanagh et al., (2013) Drug Testing and Analysis, doi:10.1002/dta.1456